Group:MUZIC:ANKRD2
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ANKRD2
Introduction
Ankyrin repeat-containing protein 2 (stretch responsive muscle) Ankrd2 belongs to the conserved muscle ankyrin repeat protein (MARP) family,[1] Also known as Arpp.[2] It is more expressed in skeletal than cardiac muscle, preferentially in type 1 fibers.[3] Ankrd2 shares approximately 50% homology with the two more MARP family members: Cardiac ankyrin repeat protein (CARP/Ankrd1) and Diabetes related ankyrin repeat protein DARP.Expression of Ankrd2/Arpp is induced in response to various forms of stress and is highly responsive to muscle mechanical status both in vivo and in vitro [1],[4], as well as to muscle plasticity induced by physical exercise [5],[6]. Apart from the mechanosensory function, Ankrd2/Arpp is a negative regulator of muscle differentiation.[7]
Structure
Ankrd2 gene contains 9 exons and spans about 12 kb. The 280 bp long region upstream of the transcription initiation site of the human Ankrd2 gene is sufficient to confer spatial and temporal expression specificity, and contains mainly cis-elements specific for the muscle-specific transcription factor MyoD and for NF-kB. [8] Ankrd2 promoter activity is significantly up-regulated by Nkx2.5 [9], upon longitudinal stretch by Akt-dependent NF-kB signaling pathway and in response to transverse stretch by Raf-1-dependent AP-1 signaling pathway. [10] The major structural characteristic of the Ankrd2 protein is the presence in the middle portion of four conserved copies of 33-residue ankyrin repeats. In addition Ankrd2 contains a coiled-coil domain that contributes to its self-dimerization, a nuclear localization signal (NLS), allowing its sorting to the nucleus, PEST protein degradation sequence and numerous potential modification sites, mainly for phosphorylation. In particular the phosphorylation of Ankrd2 by the serine/threonine kinase Akt 2 is important for its function in muscle differentiation. [11] The position of Ankrd2 phosphorylation by Akt 2 is Ser 72 which is in close proximity of calpain 3 cleavage site (Arg 77). There are many other consensus phosphorylation sites for casein kinase I (CKI), casein kinase II (CKII), protein kinase C (PKC), extracellular signal regulated kinase (ERK), cAMP- dependent protein kinase, calmodulin-dependent protein kinase II and cGMP-dependent protein kinase [2],[4]
Gene Function
Ankrd2 is involved in muscle stress response. It is up-regulated after chronic immobilization in a stretched position.[1] [6], after eccentric contraction [5] , as well as in injured muscles.[11] Denervation of slow muscle decreases the level of Ankrd2 to below the detection limit in 4 weeks [6], whereas denervation of fast muscle increases its expression.[3] Ankrd2 is not essential for the basal functioning of skeletal muscle, but it is clear its influence on the gene expression program of skeletal muscle cells.[12] Mainly the Ankrd2 protein has a major role in skeletal muscle formation as a myogenic regulator, since its over-expression in C2C12 myoblasts significantly affects and down-regulates MyoD, myogenin, and their target gene Myh1.[7] Altered expression of Ankrd2 has been found in patients suffering from inherited myopathies (muscular dystrophies (MD), congenital myopathies (CM)) and motor neuron diseases (spinal muscular atrophy (SMA), amyotrophic lateral sclerosis (ALS)).
Localization
Ankrd2 is found in the central I-band of the sarcomere, where binds the N2A region of titin. In myoblasts Ankrd2 localizes both in the nuclei, in form of speckles and in the cytoplasm [7], with a diffused pattern. As the differentiation into multinucleated myotubes progresses, Ankrd2 seems to change localization and to accumulate mainly in the cytoplasm [13]. In general, Ankrd2 protein functions by moving between the sarcomere and the nucleus, mainly in response to stress signals [14].
Ankrd2 Interactions
The Ankrd2/Arpp can interact with titin [4], telethonin/T-cap [14], calpain 3 [15], promyelocytic leukemia protein (PML)[14], YB-1 [14], p53 [14], Akt 2 [11] and zonula occludens 1 (ZO1).[9]
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Proteopedia Page Contributors and Editors (what is this?)
Spyros D. Chatziefthimiou, Narendra Kumar Verma, Nikos Pinotsis, Michal Harel, Jaime Prilusky
